Method And System For Measuring Urea

ABSTRACT

A body-mountable urea sensing device includes an electrochemical sensor embedded in a polymeric material configured for mounting to a surface of an eye. The electrochemical sensor includes a working electrode, a reference electrode, and a reagent localized near the working electrode that selectively reacts with urea. A potentiometric voltage between the working electrode and the reference electrode is related to a concentration of urea in a fluid to which the electrochemical sensor is exposed; the voltage is measured by the body-mountable device and wirelessly communicated.

BACKGROUND

Unless otherwise indicated herein, the materials described in thissection are not prior art to the claims in this application and are notadmitted to be prior art by inclusion in this section.

Electrochemical potentiometric sensors measure concentrations of ananalyte by measuring voltage differences that develop between two ormore electrodes exposed to a solution containing one or more analytes.One of the two more electrodes is a reference electrode that has a knownpotential in the solution that is substantially unchanged by changes inconcentration of the one or more analytes. Another of the two or moreelectrodes is a working electrode whose potential in the solution isselectively changed by changes in concentration of the one or moreanalytes. Substantially no current is allowed to flow through thereference and working electrodes. The voltage difference between thereference electrode and the working electrode is thus related to theconcentration of the one or more analytes in the solution. Measurementof the voltage between the reference electrode and the working electrodecan be performed by a high-impedance voltmeter.

SUMMARY

Some embodiments of the present disclosure provide a body-mountabledevice including: a shaped polymeric material; a substrate at leastpartially embedded within the shaped polymeric material; an antennadisposed on the substrate; an electrochemical sensor disposed on thesubstrate and comprising: a working electrode, a reagent thatselectively reacts with urea localized proximate to the workingelectrode, and a reference electrode; and a controller electricallyconnected to the electrochemical sensor and the antenna. The controllercan be configured to: (i) measure a potentiometric voltage between theworking electrode and the reference electrode related to theconcentration of urea in a fluid to which the body-mountable device isexposed; and (iii) use the antenna to indicate the measuredpotentiometric voltage.

Some embodiments of the present disclosure provide a method including:exposing a working electrode and a reference electrode to a fluid,wherein the working electrode and reference electrode are disposed in abody-mountable device, wherein the working electrode is selectivelysensitive to urea, wherein the body-mountable device additionallyincludes an antenna and measurement electronics, and wherein the workingelectrode, reference electrode, antenna, and measurement electronics aredisposed on a substrate that is at least partially embedded in a shapedpolymeric material; measuring a voltage between the working electrodeand the reference electrode related to the concentration of urea in thefluid to which the body-mountable device is exposed; and wirelesslyindicating the measured voltage using an antenna which is also disposedin the body-mountable device.

Some embodiments of the present disclosure provide a system comprising:an antenna configured to wirelessly communicate with a body-mountabledevice, wherein the body-mountable device is configured to measure avoltage related to the concentration of urea in a fluid to which thebody-mountable device is exposed; a processor; user controls; and anon-transitory computer readable medium containing instructions that canbe executed by the processor to cause the system to perform functionsincluding: (i) using the radio frequency antenna to interrogate thebody-mountable device by transmitting a radio frequency signal, (ii)receiving from the body-mountable device a radio-frequency signalindicating a measured voltage, (iii) determining a urea concentration inthe fluid based on the indicated measured voltage.

Some embodiments of the present disclosure provide a method including:interrogating a body-mountable device, the body-mountable deviceincluding an antenna, measurement electronics, and an electrochemicalsensor with a working electrode and a reference electrode, wherein areagent that selectively reacts with urea is localized proximate to theworking electrode, wherein the antenna, measurement electronics, and theelectrochemical sensor are disposed on a substrate that is at leastpartially embedded in a shaped polymeric material, by transmitting radiofrequency radiation sufficient to power the electrochemical sensor andmeasurement electronics to measure a voltage difference between theworking electrode and the reference electrode related to urea;receiving, from the body-mountable device, a radio frequency signalindicating the measured voltage; and determining a concentration of ureabased on the measured voltage indicated by the radio frequency signal.

Some embodiments of the present disclosure provide a method including:forming a substrate; disposing components on the substrate, wherein thecomponents include an electrochemical sensor having at least a workingelectrode and a reference electrode, measurement electronics, and aradio frequency antenna; at least partially embedding the substrate andcomponents disposed thereon in a shaped polymeric material; andlocalizing a reagent that reacts selectively with urea proximate to theworking electrode.

These as well as other aspects, advantages, and alternatives, willbecome apparent to those of ordinary skill in the art by reading thefollowing detailed description, with reference where appropriate to theaccompanying drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a block diagram of an example system that includes aneye-mountable device in wireless communication with an external reader.

FIG. 2A is a bottom view of an example eye-mountable device.

FIG. 2B is an aspect view of the example eye-mountable device shown inFIG. 2A.

FIG. 2C is a side cross-section view of the example eye-mountable deviceshown in FIGS. 2A and 2B while mounted to a corneal surface of an eye.

FIG. 2D is a side cross-section view enhanced to show the tear filmlayers surrounding the surfaces of the example eye-mountable device whenmounted as shown in FIG. 2C.

FIG. 3 is a functional block diagram of an example system forelectrochemically measuring a urea concentration in a fluid.

FIG. 4A illustrates an example arrangement for electrodes in anelectrochemical urea sensor disposed on a surface of a flattened ringsubstrate.

FIG. 4B illustrates the arrangement in FIG. 4A when embedded in apolymeric material with a channel positioned to expose theelectrochemical urea sensor electrodes.

FIG. 5 is a flowchart of an example process for operating apotentiometric urea sensor in a body-mountable device to measure a ureaconcentration in a fluid.

FIG. 6 is a flowchart of an example process for operating a system tointerrogate a potentiometric urea sensor in a body-mountable device tomeasure a urea concentration in a fluid.

FIG. 7 is a flowchart of an example process for fabricating abody-mountable device capable of potentiometrically measuring a ureaconcentration in a fluid.

DETAILED DESCRIPTION

In the following detailed description, reference is made to theaccompanying figures, which form a part hereof. In the figures, similarsymbols typically identify similar components, unless context dictatesotherwise. The illustrative embodiments described in the detaileddescription, figures, and claims are not meant to be limiting. Otherembodiments may be utilized, and other changes may be made, withoutdeparting from the scope of the subject matter presented herein. It willbe readily understood that the aspects of the present disclosure, asgenerally described herein, and illustrated in the figures, can bearranged, substituted, combined, separated, and designed in a widevariety of different configurations, all of which are explicitlycontemplated herein.

I. Overview

Some embodiments of the present disclosure provide an eye-mountabledevice configured to rest on corneal tissue, such as a contact lens,with one or more electrochemical sensors for quantitatively andqualitatively testing urea concentration in a tear film in situ and inreal-time. Those of skill in the art will recognize that the sensingplatform described herein may be provided in devices that could bemounted on portions of the human body other than the eye to measureconcentrations of urea in other fluids than a tear film of an eye. Thoseof skill in the art will also recognize that the sensing platformdescribed herein may be provided in devices that could be mounted inlocations other than locations on the human body to measureconcentrations of urea in a fluid proximate to the mounting location ofthe devices.

An ophthalmic sensing platform can include an electrochemical sensor,control electronics and an antenna all situated on a substrate embeddedin a polymeric material formed to be contact mounted to an eye. Thecontrol electronics can operate the sensor to perform measurements ofurea concentration and can operate the antenna to wirelessly communicatethe measurements from the sensor to an external reader via the antenna.

In some examples, the polymeric material can be in the form of a roundlens with a concave curvature configured to mount to a corneal surfaceof an eye. The substrate can be embedded near the periphery of thepolymeric material to avoid interference with incident light receivedcloser to the central region of the cornea. The sensor can be arrangedon the substrate to face inward, toward the corneal surface so as togenerate clinically relevant readings from near the surface of thecornea and/or from tear fluid interposed between the contact lens andthe corneal surface. Additionally or alternatively, the sensor can bearranged on the substrate to face outward, away from the corneal surfaceand toward the layer of tear fluid coating the surface of the polymericmaterial exposed to the atmosphere. In some examples, the sensor isentirely embedded within the contact lens material. For example, thesensor can be suspended in the lens material and situated such that theworking electrode is less than 10 micrometers from the polymeric surfaceconfigured to mount to the cornea. The sensor can generate an outputsignal indicative of a concentration of an analyte that diffuses throughthe lens material to the embedded sensor. In some examples, the sensoris directly exposed to the analyte-containing fluid. For example, thelens material can be formed such that a there is a window in the lensmaterial over the sensor, allowing the analyte-containing fluid todirectly contact the sensor. In another example, a channel is formed inthe lens material from the surface of the lens material to the sensor,allowing the analyte-containing fluid to fill the channel. In thisexample, the sensor can generate an output signal indicative of aconcentration of an analyte in the fluid in the channel.

In some examples, the electrochemical sensor disposed in the ophthalmicsensing platform can include a working electrode sensitive to urea and areference electrode. By exposing the sensing platform to a target fluid,a potentiometric voltage is developed that can indicate theconcentration of urea near the working electrode. The working electrodecan be made sensitive to urea by localizing a reagent selectivelyreactive with urea near a working electrode of the sensor. In someexamples, the enzyme urease can be deposited onto particles of apH-sensitive oxide nano-powder that is disposed on the workingelectrode. In those examples, the urease selectively reacts with urea,creating products including ammonia. The ammonia then interacts with theworking electrode, resulting in a voltage that can be related to theconcentration of urea near the working electrode.

The ophthalmic sensing platform can be powered via one or more batteriesin the sensing platform or by energy from an external source. Forexample, power can be provided by light energizing photovoltaic cellsincluded on the sensing platform. Additionally or alternatively, powercan be provided by radio frequency energy harvested from the antenna. Arectifier and/or regulator can be incorporated with the controlelectronics to generate a stable DC voltage to power the sensingplatform from the harvested energy. The antenna can be arranged as aloop of conductive material with leads connected to the controlelectronics. In some embodiments, such a loop antenna can wirelesslyalso communicate the sensor readings to an external reader by modifyingthe impedance of the loop antenna so as to modify backscatter radiationfrom the antenna.

In some examples, an external reader can radiate radio frequencyradiation to power the ophthalmic sensing platform via the energyharvesting system. The external reader may thereby control the operationof the sensing platform by controlling the supply of power to thesensing platform. In some examples, the external reader can operate tointermittently interrogate the sensing platform to provide a reading byradiating sufficient radiation to power the sensing platform to obtain ameasurement and communicate the result. The external reader can alsostore the sensor results communicated by the sensing platform. In thisway, the external reader can acquire a series of urea concentrationmeasurements over time without continuously powering the sensingplatform.

The external reader may be provided as a mobile device with softwareapplications for displaying the sensor results. The external reader mayalso include a communications interface that can be configured to conveythe measured urea concentrations to other systems for display, datastorage, and/or analysis.

II. Example Ophthalmic Electronics Platform

FIG. 1 is a block diagram of a system 100 that includes an eye-mountabledevice 110 in wireless communication with an external reader 180. Theexposed regions of the eye-mountable device 110 are made of a polymericmaterial 120 formed to be contact-mounted to a corneal surface of aneye. A substrate 130 is embedded in the polymeric material 120 toprovide a mounting surface for a power supply 140, a controller 150,bio-interactive electronics 160, and a communication antenna 170. Thebio-interactive electronics 160 are operated by the controller 150. Thepower supply 140 supplies operating voltages to the controller 150and/or the bio-interactive electronics 160. The antenna 170 is operatedby the controller 150 to communicate information to and/or from theeye-mountable device 110. The antenna 170, the controller 150, the powersupply 140, and the bio-interactive electronics 160 can all be situatedon the embedded substrate 130. Because the eye-mountable device 110includes electronics and is configured to be contact-mounted to an eye,it is also referred to herein as an ophthalmic electronics platform.

To facilitate contact-mounting, the polymeric material 120 can have aconcave surface configured to adhere (“mount”) to a moistened cornealsurface (e.g., by capillary forces with a tear film coating the cornealsurface). Additionally or alternatively, the eye-mountable device 110can be adhered by a vacuum force between the corneal surface and thepolymeric material due to the concave curvature. While mounted with theconcave surface against the eye, the outward-facing surface of thepolymeric material 120 can have a convex curvature that is formed to notinterfere with eye-lid motion while the eye-mountable device 110 ismounted to the eye. For example, the polymeric material 120 can be asubstantially transparent curved polymeric disk shaped similarly to acontact lens.

The polymeric material 120 can include one or more biocompatiblematerials, such as those employed for use in contact lenses or otherophthalmic applications involving direct contact with the cornealsurface. The polymeric material 120 can optionally be formed in partfrom such biocompatible materials or can include an outer coating withsuch biocompatible materials. The polymeric material 120 can includematerials configured to moisturize the corneal surface, such ashydrogels and the like. In some instances, the polymeric material 120can be a deformable (“non-rigid”) material to enhance wearer comfort. Insome instances, the polymeric material 120 can be shaped to provide apredetermined, vision-correcting optical power, such as can be providedby a contact lens.

The substrate 130 includes one or more surfaces suitable for mountingthe bio-interactive electronics 160, the controller 150, the powersupply 140, and the antenna 170. The substrate 130 can be employed bothas a mounting platform for chip-based circuitry (e.g., by flip-chipmounting) and/or as a platform for patterning conductive materials(e.g., gold, platinum, palladium, titanium, copper, aluminum, silver,metals, other conductive materials, combinations of these, etc.) tocreate electrodes, interconnects, antennae, etc. In some embodiments,substantially transparent conductive materials (e.g., indium tin oxide)can be patterned on the substrate 130 to form circuitry, electrodes,etc. For example, the antenna 170 can be formed by depositing a patternof gold or another conductive material on the substrate 130. Similarly,interconnects 151, 157 between the controller 150 and thebio-interactive electronics 160, and between the controller 150 and theantenna 170, respectively, can be formed by depositing suitable patternsof conductive materials on the substrate 130. A combination ofmicrofabrication techniques including, without limitation, the use ofphotoresists, masks, deposition techniques and/or plating techniques canbe employed to pattern materials on the substrate 130. The substrate 130can be a relatively rigid material, such as polyethylene terephthalate(“PET”), parylene, or another material sufficient to structurallysupport the circuitry and/or electronics within the polymeric material120. The eye-mountable device 110 can alternatively be arranged with agroup of unconnected substrates rather than a single substrate. Forexample, the controller 150 and a bio-sensor or other bio-interactiveelectronic component can be mounted to one substrate, while the antenna170 is mounted to another substrate and the two can be electricallyconnected via the interconnects 157.

In some embodiments, the bio-interactive electronics 160 (and thesubstrate 130) can be positioned away from the center of theeye-mountable device 110 and thereby avoid interference with lighttransmission to the eye through the center of the eye-mountable device110. For example, where the eye-mountable device 110 is shaped as aconcave-curved disk, the substrate 130 can be embedded around theperiphery (e.g., near the outer circumference) of the disk. In someembodiments, the bio-interactive electronics 160 (and the substrate 130)can be positioned in the center region of the eye-mountable device 110.The bio-interactive electronics 160 and/or substrate 130 can besubstantially transparent to incoming visible light to mitigateinterference with light transmission to the eye. Moreover, in someembodiments, the bio-interactive electronics 160 can include a pixelarray 164 that emits and/or transmits light to be perceived by the eyeaccording to display instructions. Thus, the bio-interactive electronics160 can optionally be positioned in the center of the eye-mountabledevice so as to generate perceivable visual cues to a wearer of theeye-mountable device 110, such as by displaying information via thepixel array 164.

The substrate 130 can be shaped as a flattened ring with a radial widthdimension sufficient to provide a mounting platform for the embeddedelectronics components. The substrate 130 can have a thicknesssufficiently small to allow the substrate 130 to be embedded in thepolymeric material 120 without influencing the profile of theeye-mountable device 110. The substrate 130 can have a thicknesssufficiently large to provide structural stability suitable forsupporting the electronics mounted thereon. For example, the substrate130 can be shaped as a ring with a diameter of about 10 millimeters, aradial width of about 1 millimeter (e.g., an outer radius 1 millimeterlarger than an inner radius), and a thickness of about 50 micrometers.The substrate 130 can optionally be aligned with the curvature of theeye-mounting surface of the eye-mountable device 110 (e.g., convexsurface). For example, the substrate 130 can be shaped along the surfaceof an imaginary cone between two circular segments that define an innerradius and an outer radius. In such an example, the surface of thesubstrate 130 along the surface of the imaginary cone defines aninclined surface that is approximately aligned with the curvature of theeye mounting surface at that radius.

The power supply 140 is configured to harvest energy to power thecontroller 150 and bio-interactive electronics 160. For example, aradio-frequency energy-harvesting antenna 142 can capture energy fromincident radio radiation. Additionally or alternatively, solar cell(s)144 (“photovoltaic cells”) can capture energy from incoming ultraviolet,visible, and/or infrared radiation. Furthermore, an inertial powerscavenging system can be included to capture energy from ambientvibrations. The energy harvesting antenna 142 can optionally be adual-purpose antenna that is also used to communicate information to theexternal reader 180. That is, the functions of the communication antenna170 and the energy harvesting antenna 142 can be accomplished with thesame physical antenna.

A rectifier/regulator 146 can be used to condition the captured energyto a stable DC supply voltage 141 that is supplied to the controller150. For example, the energy harvesting antenna 142 can receive incidentradio frequency radiation. Varying electrical signals on the leads ofthe antenna 142 are output to the rectifier/regulator 146. Therectifier/regulator 146 rectifies the varying electrical signals to a DCvoltage and regulates the rectified DC voltage to a level suitable foroperating the controller 150. Additionally or alternatively, outputvoltage from the solar cell(s) 144 can be regulated to a level suitablefor operating the controller 150. The rectifier/regulator 146 caninclude one or more energy storage devices to mitigate high frequencyvariations in the ambient energy gathering antenna 142 and/or solarcell(s) 144. For example, one or more energy storage devices (e.g., acapacitor, an inductor, etc.) can be connected in parallel across theoutputs of the rectifier 146 to regulate the DC supply voltage 141 andconfigured to function as a low-pass filter.

The controller 150 is turned on when the DC supply voltage 141 isprovided to the controller 150, and the logic in the controller 150operates the bio-interactive electronics 160 and the antenna 170. Thecontroller 150 can include logic circuitry configured to operate thebio-interactive electronics 160 so as to interact with a biologicalenvironment of the eye-mountable device 110. The interaction couldinvolve the use of one or more components, such an electrochemical ureasensor 162, in bio-interactive electronics 160 to obtain input from thebiological environment. Additionally or alternatively, the interactioncould involve the use of one or more components, such as pixel array164, to provide an output to the biological environment.

In one example, the controller 150 includes a sensor interface module152 that is configured to operate electrochemical urea sensor 162. Theelectrochemical urea sensor 162 can be, for example, a potentiometricsensor that includes a working electrode and a reference electrode. Avoltage can develop between the working and reference electrodes inresponse to a concentration of an analyte in a fluid to which theworking electrode is exposed. Thus, the magnitude of the potentiometricvoltage that is measured between the working electrode and the referenceelectrode can provide an indication of analyte concentration. In someembodiments, the sensor interface module 152 can be a high-impedancevoltmeter configured to measure the voltage difference between workingand reference electrodes while substantially preventing the flow ofcurrent through the working and reference electrodes.

In some instances, a reagent can also be included to sensitize theelectrochemical sensor to urea. In one example, urease localizedproximate to the working electrode can catalyze urea into ammonium (NH₄⁺) and ammonium hydroxide (NH₄OH). The ammonium hydroxide can cause anincrease in pH near the working electrode. The increase in pH can thenbe detected by a pH-responsive working electrode, resulting in anequilibrium potentiometric voltage that can be measured between theworking electrode and the reference electrode.

The equilibrium voltage in an example potentiometric electrochemicalurea sensor is related to the concentration of urea near the workingelectrode. The relationship between voltage and concentration can bedetermined experimentally for individual electrochemical urea sensors ordetermined once for an example sensor or sensors and the calibrationfrom the example sensor or sensors can be applied to otherelectrochemical urea sensors.

The controller 150 can optionally include a display driver module 154for operating a pixel array 164. The pixel array 164 can be an array ofseparately programmable light transmitting, light reflecting, and/orlight emitting pixels arranged in rows and columns. The individual pixelcircuits can optionally include liquid crystal technologies,microelectromechanical technologies, emissive diode technologies, etc.to selectively transmit, reflect, and/or emit light according toinformation from the display driver module 154. Such a pixel array 164can also optionally include more than one color of pixels (e.g., red,green, and blue pixels) to render visual content in color. The displaydriver module 154 can include, for example, one or more data linesproviding programming information to the separately programmed pixels inthe pixel array 164 and one or more addressing lines for setting groupsof pixels to receive such programming information. Such a pixel array164 situated on the eye can also include one or more lenses to directlight from the pixel array to a focal plane perceivable by the eye.

The controller 150 can also include a communication circuit 156 forsending and/or receiving information via the antenna 170. Thecommunication circuit 156 can optionally include one or moreoscillators, mixers, frequency injectors, etc. to modulate and/ordemodulate information on a carrier frequency to be transmitted and/orreceived by the antenna 170. In some examples, the eye-mountable device110 is configured to indicate an output from a bio-sensor by modulatingan impedance of the antenna 170 in a manner that is perceivably by theexternal reader 180. For example, the communication circuit 156 cancause variations in the amplitude, phase, and/or frequency ofbackscatter radiation from the antenna 170, and such variations can bedetected by the reader 180.

The controller 150 is connected to the bio-interactive electronics 160via interconnects 151. For example, where the controller 150 includeslogic elements implemented in an integrated circuit to form the sensorinterface module 152 and/or display driver module 154, a patternedconductive material (e.g., gold, platinum, palladium, titanium, copper,aluminum, silver, metals, combinations of these, etc.) can connect aterminal on the chip to the bio-interactive electronics 160. Similarly,the controller 150 is connected to the antenna 170 via interconnects157.

It is noted that the block diagram shown in FIG. 1 is described inconnection with functional modules for convenience in description.However, embodiments of the eye-mountable device 110 can be arrangedwith one or more of the functional modules (“sub-systems”) implementedin a single chip, integrated circuit, and/or physical feature. Forexample, while the rectifier/regulator 146 is illustrated in the powersupply block 140, the rectifier/regulator 146 can be implemented in achip that also includes the logic elements of the controller 150 and/orother features of the embedded electronics in the eye-mountable device110. Thus, the DC supply voltage 141 that is provided to the controller150 from the power supply 140 can be a supply voltage that is providedon a chip by rectifier and/or regulator components the same chip. Thatis, the functional blocks in FIG. 1 shown as the power supply block 140and controller block 150 need not be implemented as separated modules.Moreover, one or more of the functional modules described in FIG. 1 canbe implemented by separately packaged chips electrically connected toone another.

Additionally or alternatively, the energy harvesting antenna 142 and thecommunication antenna 170 can be implemented with the same physicalantenna. For example, a loop antenna can both harvest incident radiationfor power generation and communicate information via backscatterradiation.

The external reader 180 includes an antenna 188 (or group of more thanone antennae) to send and receive wireless signals 171 to and from theeye-mountable device 110. The external reader 180 also includes acomputing system with a processor 186 in communication with a memory182. The external reader 180 can also include one or more of usercontrols 185, a display 187, and a communication interface 189. Thememory 182 is a non-transitory computer-readable medium that caninclude, without limitation, magnetic disks, optical disks, organicmemory, and/or any other volatile (e.g. RAM) or non-volatile (e.g. ROM)storage system readable by the processor 186. The memory 182 can includea data storage 183 to store indications of data, such as sensor readings(e.g., from the electrochemical urea sensor 162), program settings(e.g., to adjust behavior of the eye-mountable device 110 and/orexternal reader 180), etc. The memory 182 can also include programinstructions 184 for execution by the processor 186 to cause theexternal reader 180 to perform processes specified by the instructions184. For example, the program instructions 184 can cause external reader180 to perform any of the function described herein. For example,program instructions 184 may cause the external reader 180 to provide auser interface that allows for retrieving information communicated fromthe eye-mountable device 110 (e.g., sensor outputs from theelectrochemical urea sensor 162) by displaying that information on thedisplay 187 in response to commands input through the user controls 185.The external reader 180 can also include one or more hardware componentsfor operating the antenna 188 to send and receive the wireless signals171 to and from the eye-mountable device 110. For example, oscillators,frequency injectors, encoders, decoders, amplifiers, filters, etc. candrive the antenna 188 according to instructions from the processor 186.

The external reader 180 can also be configured include a communicationinterface 189 to communicate signals via a communication medium 191 toand from a remote system 190. For example, the remote system 190 may bea smart phone, tablet computer, laptop computer, or personal computer,and communication interface 189 and communication medium 191 may be aBluetooth module and wireless Bluetooth communication signals,respectively. In this example, the external reader 180 may be configuredto send urea concentration data collected by the biosensor 160 to thesmart phone, tablet computer, laptop computer, or personal computer forstorage and offline analysis. In another example, the remote system 190is a server at a clinic or physician's office, the communicationinterface 189 is a WiFi radio module, and the communication medium 191is elements of the internet sufficient to enable the transfer of databetween the remote server and the WiFi radio module. A physician may usethis data to make determinations or diagnoses related to the subject'scondition. Further, the external reader 180 may be configured to receivesignals from a remote server, such as instructions sent by a physicianat a remote location to, for example, increase or decrease samplingfrequency. Communication interface 189 could be configured to enableother forms of wired or wireless communication; for example, CDMA, EVDO,GSM/GPRS, WiMAX, LTE, infrared, ZigBee, Ethernet, USB, FireWire, a wiredserial link, or near field communication.

The external reader 180 can be a smart phone, digital assistant, orother portable computing device with wireless connectivity sufficient toprovide the wireless communication link 171. The external reader 180 canalso be implemented as an antenna module that can be plugged in to aportable computing device, such as in an example where the communicationlink 171 operates at carrier frequencies not commonly employed inportable computing devices. In some instances, the external reader 180is a special-purpose device configured to be worn relatively near awearer's eye to allow the wireless communication link 171 to operatewith a low power budget. For example, the external reader 180 can beintegrated in a piece of jewelry such as a necklace, earing, etc. orintegrated in an article of clothing worn near the head, such as a hat,headband, etc. The external reader 180 could also be implemented in eyeglasses or a head-mounted display.

In an example where the eye-mountable device 110 includes anelectrochemical urea sensor 162, the system 100 can be operated tomeasure the urea concentration in a tear film on the surface of the eye.The tear film is an aqueous layer secreted from the lacrimal gland tocoat the eye. The tear film is in contact with the blood supply throughcapillaries in the structure of the eye and includes many biomarkersfound in blood that are analyzed to characterize a person's healthcondition(s). For example, the tear film includes urea, glucose,calcium, sodium, cholesterol, potassium, other biomarkers, etc. Thebiomarker concentrations in the tear film can be systematicallydifferent than the corresponding concentrations of the biomarkers in theblood, but a relationship between the two concentration levels can beestablished to map tear film biomarker concentration values to bloodconcentration levels. For example, the tear film concentration of ureacan be established (e.g., empirically determined) to be approximatelyone tenth the corresponding blood urea concentration. Thus, measuringtear film yrea concentration levels provides a non-invasive techniquefor monitoring urea levels in comparison to blood sampling techniquesperformed by lancing a volume of blood to be analyzed outside a person'sbody. Moreover, the ophthalmic urea bio-sensor platform disclosed herecan be operated substantially continuously to enable real timemeasurement of urea concentrations.

To perform a reading with the system 100 configured as a tear film ureasensor, the external reader 180 can emit radio frequency radiation 171that is harvested to power the eye-mountable device 110 via the powersupply 140. Radio frequency electrical signals captured by the energyharvesting antenna 142 (and/or the communication antenna 170) arerectified and/or regulated in the rectifier/regulator 146 and aregulated DC supply voltage 147 is provided to the controller 150. Theradio frequency radiation 171 thus powers the electronic componentswithin the eye-mountable device 110. Once powered, the controller 150operates the urea sensor 162 to measure a urea concentration level. Forexample, the sensor interface module 152 can measure the voltage betweena working electrode and a reference electrode in the urea sensor 162.The measured potentiometric voltage can provide the sensor reading(“result”) indicative of the urea concentration. The controller 150 canoperate the antenna 170 to communicate the sensor reading back to theexternal reader 180 (e.g., via the communication circuit 156). Thesensor reading can be communicated by, for example, modulating animpedance of the communication antenna 170 such that the modulation inimpedance is detected by the external reader 180. The modulation inantenna impedance can be detected by, for example, backscatter radiationfrom the antenna 170.

In some embodiments, the system 100 can operate to non-continuously(“intermittently”) supply energy to the eye-mountable device 110 topower the controller 150 and electronics 160. For example, radiofrequency radiation 171 can be supplied to power the eye-mountabledevice 110 long enough to carry out a tear film urea concentrationmeasurement and communicate the results. For example, the supplied radiofrequency radiation can provide sufficient power to measure thepotentiometric voltage between the working and reference electrodes andmodulate the antenna impedance to adjust the backscatter radiation in amanner indicative of the measured potentiometric voltage. In such anexample, the supplied radio frequency radiation 171 can be considered aninterrogation signal from the external reader 180 to the eye-mountabledevice 110 to request a measurement. By periodically interrogating theeye-mountable device 110 (e.g., by supplying radio frequency radiation171 to temporarily turn the device on) and storing the sensor results(e.g., via the data storage 183), the external reader 180 can accumulatea set of analyte concentration measurements over time withoutcontinuously powering the eye-mountable device 110.

In other embodiments, the system 100 can operate continuously and supplyenergy to the eye-mountable device 110 to power the controller 150 andelectronics 160 at all times. In some instances, it may be desirable tocontinuously measure urea concentration and collect, store, and ortransmit this data.

FIG. 2A is a bottom view of an example eye-mountable electronic device210. FIG. 2B is an aspect view of the example eye-mountable electronicdevice shown in FIG. 2A. It is noted that relative dimensions in FIGS.2A and 2B are not necessarily to scale, but have been rendered forpurposes of explanation only in describing the arrangement of theexample eye-mountable electronic device 210. The eye-mountable device210 is formed of a polymeric material 220 shaped as a curved disk. Thepolymeric material 220 can be a substantially transparent material toallow incident light to be transmitted to the eye while theeye-mountable device 210 is mounted to the eye. The polymeric material220 can be a biocompatible material similar to those employed to formvision correction and/or cosmetic contact lenses in optometry, such aspolyethylene terephthalate (“PET”), polymethyl methacrylate (“PMMA”),silicone hydrogels, combinations of these, etc. The polymeric material220 can be formed with one side having a concave surface 226 suitable tofit over a corneal surface of an eye. The opposing side of the disk canhave a convex surface 224 that does not interfere with eyelid motionwhile the eye-mountable device 210 is mounted to the eye. A circularouter side edge 228 connects the concave surface 224 and convex surface226.

The eye-mountable device 210 can have dimensions similar to a visioncorrection and/or cosmetic contact lenses, such as a diameter ofapproximately 1 centimeter, and a thickness of about 0.1 to about 0.5millimeters. However, the diameter and thickness values are provided forexplanatory purposes only. In some embodiments, the dimensions of theeye-mountable device 210 can be selected according to the size and/orshape of the corneal surface of the wearer's eye.

The polymeric material 220 can be formed with a curved shape in avariety of ways. For example, techniques similar to those employed toform vision-correction contact lenses, such as heat molding, injectionmolding, spin casting, etc. can be employed to form the polymericmaterial 220. While the eye-mountable device 210 is mounted in an eye,the convex surface 224 faces outward to the ambient environment whilethe concave surface 226 faces inward, toward the corneal surface. Theconvex surface 224 can therefore be considered an outer, top surface ofthe eye-mountable device 210 whereas the concave surface 226 can beconsidered an inner, bottom surface. The “bottom” view shown in FIG. 2Ais facing the concave surface 226. From the bottom view shown in FIG.2A, the outer periphery 222, near the outer circumference of the curveddisk is curved out of the page, whereas the center region 221, near thecenter of the disk is curved in to the page.

A substrate 230 is embedded in the polymeric material 220. The substrate230 can be embedded to be situated along the outer periphery 222 of thepolymeric material 220, away from the center region 221. The substrate230 does not interfere with vision because it is too close to the eye tobe in focus and is positioned away from the center region 221 whereincident light is transmitted to the eye-sensing portions of the eye.Moreover, the substrate 230 can be formed of a transparent material tofurther mitigate any effects on visual perception.

The substrate 230 can be shaped as a flat, circular ring (e.g., a diskwith a central hole). The flat surface of the substrate 230 (e.g., alongthe radial width) is a platform for mounting electronics such as chips(e.g., via flip-chip mounting) and for patterning conductive materials(e.g., via deposition techniques) to form electrodes, antenna(e), and/orconnections. The substrate 230 and the polymeric material 220 can beapproximately cylindrically symmetric about a common central axis. Thesubstrate 230 can have, for example, a diameter of about 10 millimeters,a radial width of about 1 millimeter (e.g., an outer radius 1 millimetergreater than an inner radius), and a thickness of about 50 micrometers.However, these dimensions are provided for example purposes only, and inno way limit the present disclosure. The substrate 230 can beimplemented in a variety of different form factors.

A loop antenna 270, controller 250, and bio-interactive electronics 260are disposed on the embedded substrate 230. The controller 250 can be achip including logic elements configured to operate the bio-interactiveelectronics 260 and the loop antenna 270. The controller 250 iselectrically connected to the loop antenna 270 by interconnects 257 alsosituated on the substrate 230. Similarly, the controller 250 iselectrically connected to the bio-interactive electronics 260 by aninterconnect 251. The interconnects 251, 257, the loop antenna 270, andany conductive electrodes (e.g., for an electrochemical urea sensor,etc.) can be formed from conductive materials patterned on the substrate230 by a process for precisely patterning such materials, such asdeposition, lithography, etc. The conductive materials patterned on thesubstrate 230 can be, for example, gold, platinum, palladium, titanium,carbon, aluminum, copper, silver, silver-chloride, conductors formedfrom noble materials, metals, combinations of these, etc.

As shown in FIG. 2A, which is a view facing the concave surface 226 ofthe eye-mountable device 210, the bio-interactive electronics module 260is mounted to a side of the substrate 230 facing the concave surface226. Where the bio-interactive electronics module 260 includes a ureasensor, for example, mounting such a sensor on the substrate 230 to beclose to the concave surface 226 allows the sensor to sense ureaconcentrations in tear film near the surface of the eye. However, theelectronics, electrodes, etc. situated on the substrate 230 can bemounted to either the “inward” facing side (e.g., situated closest tothe concave surface 226) or the “outward” facing side (e.g., situatedclosest to the convex surface 224). Moreover, in some embodiments, someelectronic components can be mounted on one side of the substrate 230,while other electronic components are mounted to the opposing side, andconnections between the two can be made via conductive materials passingthrough the substrate 230.

The loop antenna 270 can be a layer of conductive material patternedalong the flat surface of the substrate to form a flat conductive ring.In some instances, the loop antenna 270 can be formed without making acomplete loop. For instance, the antenna 270 can have a cutout to allowroom for the controller 250 and bio-interactive electronics 260, asillustrated in FIG. 2A. However, the loop antenna 270 can also bearranged as a continuous strip of conductive material that wrapsentirely around the flat surface of the substrate 230 one or more times.For example, a strip of conductive material with multiple windings canbe patterned on the side of the substrate 230 opposite the controller250 and bio-interactive electronics 260. Interconnects between the endsof such a wound antenna (e.g., the antenna leads) can be passed throughthe substrate 230 to the controller 250.

FIG. 2C is a side cross-section view of the example eye-mountableelectronic device 210 while mounted to a corneal surface 22 of an eye10. FIG. 2D is a close-in side cross-section view enhanced to show thetear film layers 40, 42 surrounding the exposed surfaces 224, 226 of theexample eye-mountable device 210. It is noted that relative dimensionsin FIGS. 2C and 2D are not necessarily to scale, but have been renderedfor purposes of explanation only in describing the arrangement of theexample eye-mountable electronic device 210. For example, the totalthickness of the eye-mountable device can be about 200 micrometers,while the thickness of the tear film layers 40, 42 can each be about 10micrometers, although this ratio may not be reflected in the drawings.Some aspects are exaggerated to allow for illustration and facilitateexplanation.

The eye 10 includes a cornea 20 that is covered by bringing the uppereyelid 30 and lower eyelid 32 together over the top of the eye 10.Incident light is received by the eye 10 through the cornea 20, wherelight is optically directed to light sensing elements of the eye 10(e.g., rods and cones, etc.) to stimulate visual perception. The motionof the eyelids 30, 32 distributes a tear film across the exposed cornealsurface 22 of the eye 10. The tear film is an aqueous solution secretedby the lacrimal gland to protect and lubricate the eye 10. When theeye-mountable device 210 is mounted in the eye 10, the tear film coatsboth the concave and convex surfaces 224, 226 with an inner layer 40(along the concave surface 226) and an outer layer 42 (along the convexlayer 224). The tear film layers 40, 42 can be about 10 micrometers inthickness and together account for about 10 microliters.

The tear film layers 40, 42 are distributed across the corneal surface22 and/or the convex surface 224 by motion of the eyelids 30, 32. Forexample, the eyelids 30, 32 raise and lower, respectively, to spread asmall volume of tear film across the corneal surface 22 and/or theconvex surface 224 of the eye-mountable device 210. The tear film layer40 on the corneal surface 22 also facilitates mounting the eye-mountabledevice 210 by capillary forces between the concave surface 226 and thecorneal surface 22. In some embodiments, the eye-mountable device 210can also be held over the eye in part by vacuum forces against cornealsurface 22 due to the concave curvature of the eye-facing concavesurface 226.

As shown in the cross-sectional views in FIGS. 2C and 2D, the substrate230 can be inclined such that the flat mounting surfaces of thesubstrate 230 are approximately parallel to the adjacent portion of theconcave surface 226. As described above, the substrate 230 is aflattened ring with an inward-facing surface 232 (closer to the concavesurface 226 of the polymeric material 220) and an outward-facing surface234 (closer to the convex surface 224). The substrate 230 can haveelectronic components and/or patterned conductive materials mounted toeither or both mounting surfaces 232, 234. As shown in FIG. 2D, thebio-interactive electronics 260, controller 250, and conductiveinterconnect 251 are mounted on the outward-facing surface 234 such thatthe bio-interactive electronics 260 are relatively closer in proximityto the outer tear film layer 42 than if they were mounted on theinward-facing surface 232. With this arrangement, the bio-interactiveelectronics 260 can receive urea concentrations in the outer tear film42 through the channel 272. However, in other examples, thebio-interactive electronics 260 may be mounted on the inward-facingsurface 232 of the substrate 230 such that the bio-interactiveelectronics 260 are facing the concave surface 226 and able to receiveurea concentrations from the inner tear film 40.

Bio-interactive electronics 260 can be made selectively sensitive tourea by localizing a reagent which selectively reacts with urea near thebio-interactive electronics 260. As shown in FIG. 2D, a reagent layer261 can be located proximate to the bio-interactive electronics 260. Thereagent layer 261 can be permeable to urea and contain reagents whichselectively react with urea to create analytes which can be senseddirectly by the bio-interactive electronics 260. In some examples, thereagent layer 261 is comprised of a nano-powder of zinc oxide andcontains a reagent which selectively reacts with urea comprising urease.Urea from the outer tear layer 42 diffuses through the channel 272 toreact selectively with the urease in the reagent layer 261; thisreaction creates products including ammonia which can be detectedpotentiometrically by the zinc oxide nano-powder on a working electrodewhich is part of the bio-interactive electronics 260. Other chemicalcompositions can be used to comprise the reagent layer 261, and otherurea-selective reagents can be disposed within the reagent layer 261,than have been disclosed above. For example, iridium oxide could be usedin place of zinc oxide to detect the pH change which occurs near thereagent layer 261 due to the generation of ammonia in the reagent layer261 by the decomposition of urea by urease. A protective layer 263 whichis permeable to urea can be disposed on the reagent layer 261. Theprotective layer 263 can be composed of a polymer that is permeable tourea. The polymer may be formulated to include porogens to tailor thepermeability to urea of the protective layer 263 for a specificapplication.

III. A Body-Mountable Electrochemical Urea Sensor

FIG. 3 is a functional block diagram of a system 300 forelectrochemically measuring a urea concentration in a fluid. The system300 includes a body-mountable device 310 with embedded electroniccomponents powered by an external reader 340. The body-mountable device310 includes an antenna 312 for capturing radio frequency radiation 341from the external reader 340. The body-mountable device 310 includes arectifier 314, an energy storage element 316, and a regulator 318 forgenerating power supply voltages 330, 332 to operate the embeddedelectronics. The body-mountable device 310 includes an electrochemicalsensor 320 with a working electrode 322 and a reference electrode 323driven by a sensor interface 321. The body-mountable device 310 includeshardware logic 324 for communicating results from the sensor 320 to theexternal reader 340 by modulating (by means of modulation electronicsand interconnects 325) the impedance of the antenna 312. Similar to theeye-mountable devices 110, 210 discussed above in connection with FIGS.1 and 2, the body-mountable device 310 can include a mounting substrateembedded within a polymeric material configured to be mounted to an eye.The electrochemical sensor 320 can be situated on a mounting surface ofsuch a substrate distal to the surface of the eye (e.g., correspondingto the bio-interactive electronics 260 on the outward-facing side 234 ofthe substrate 230) to measure analyte concentration in a tear film layercoating the exposed surface of the body-mountable device 310 on the eye(e.g., the outer tear film layer 42 interposed between the convexsurface 224 of the polymeric material 210 and the atmosphere and/orclosed eyelids). Alternatively, the electrochemical sensor 320 can besituated on a mounting surface of such a substrate proximal to thesurface of the eye (e.g., on the inward-facing side 232 of the substrate230) to measure urea concentration in a tear film layer interposedbetween the body-mountable device 310 and the eye (e.g., the inner tearfilm layer 40 between the eye-mountable device 210 and the cornealsurface 22).

With reference to FIG. 3, the electrochemical sensor 320 measures ureaconcentration by measuring a potentiometric voltage between theelectrodes 322, 323 that is caused by products of a reaction of theanalyte catalyzed by the reagent at the working electrode 322. Thesensor interface 321 measures the potentiometric voltage and provides anoutput to the hardware logic 324. The sensor interface 321 can include,for example, a high-impedance voltmeter connected to both electrodes322, 323 to measure the equilibrium potentiometric voltage between theworking electrode 322 and the reference electrode 323.

The rectifier 314, energy storage 316, and voltage regulator 318 operateto harvest energy from received radio frequency radiation 341. The radiofrequency radiation 341 causes radio frequency electrical signals onleads of the antenna 312. The rectifier 314 is connected to the antennaleads and converts the radio frequency electrical signals to a DCvoltage. The energy storage element 316 (e.g., capacitor) is connectedacross the output of the rectifier 314 to filter high frequency noise onthe DC voltage. The regulator 318 receives the filtered DC voltage andoutputs both a digital supply voltage 330 to operate the hardware logic324 and an analog supply voltage 332 to operate the electrochemicalsensor 320. For example, the analog supply voltage can be a voltage usedby the sensor interface 321 to operate a high-impedance voltmeterconnected to the sensor electrodes 322, 323 to measure a potentiometricvoltage. The digital supply voltage 330 can be a voltage suitable fordriving digital logic circuitry, such as approximately 1.2 volts,approximately 3 volts, etc. Reception of the radio frequency radiation341 from the external reader 340 (or another source, such as ambientradiation, etc.) causes the supply voltages 330, 332 to be supplied tothe sensor 320 and hardware logic 324. While powered, the sensor 320 andhardware logic 324 are configured to measure a potentiometric voltageand communicate the results.

The sensor results can be communicated back to the external reader 340via backscatter radiation 343 from the antenna 312. The hardware logic324 receives the output voltage from the electrochemical sensor 320 andmodulates (325) the impedance of the antenna 312 in accordance with thepotentiometric voltage measured by the sensor 320. The antenna impedanceand/or change in antenna impedance is detected by the external reader340 via the backscatter signal 343. The external reader 340 can includean antenna front end 342 and logic components 344 to decode theinformation indicated by the backscatter signal 343 and provide digitalinputs to a processing system 346. The external reader 340 associatesthe backscatter signal 343 with the sensor result (e.g., via theprocessing system 346 according to a pre-programmed relationshipassociating impedance of the antenna 312 with output from the sensor320). The processing system 346 can then store the indicated sensorresults (e.g., tear film analyte concentration values) in a local memoryand/or a network-connected memory. Alternatively, the sensor results canbe communicated back to the external reader 340 via an internallygenerated radio frequency signal 343 from the antenna 312.

In some embodiments, one or more of the features shown as separatefunctional blocks can be implemented (“packaged”) on a single chip. Forexample, the body-mountable device 310 can be implemented with therectifier 314, energy storage 316, voltage regulator 318, sensorinterface 321, and the hardware logic 324 packaged together in a singlechip or controller module. Such a controller can have interconnects(“leads”) connected to the loop antenna 312 and the sensor electrodes322, 323. Such a controller operates to harvest energy received at theloop antenna 312, measure a potentiometric voltage between theelectrodes 322, 323, and indicate the measured voltage via the antenna312 (e.g., through backscatter radiation 343).

IV. Example Electrochemical Urea Sensor

FIG. 4A illustrates an example arrangement for electrodes in anelectrochemical urea sensor disposed on a surface of a flattened ringsubstrate. FIG. 4A illustrates a portion of a substrate 405 on which anelectrochemical urea sensor is mounted. The substrate 405 is configuredto be embedded in an eye-mountable device and can be similar to thesubstrate 220 described above in connection with FIG. 2. The substrate405 can be shaped as a flattened ring with an inner edge 402 and anouter edge 404. The two edges 402, 404 may both be at leastapproximately circular, although only a portion of each is shown in FIG.4A.

The substrate 405 provides a mounting surface for mounting a chip 410and for patterning sensor electrodes, an antenna, and conductiveinterconnects between pads or terminals on the chip 410 and the othercomponents. An electrochemical urea sensor includes a working electrode420 and a reference electrode 430 patterned on the substrate 405. Theworking electrode 420 is electrically connected to a connection pad ofthe chip 410 through a pair of overlapped interconnects 444, 446. Thereference electrode 430 can then be electrically connected to anotherpad (not visible) on the chip 410 via the interconnect 440 that connectsto the reference electrode 430 at multiple overlap points 442.

The chip 410 can also be connected to other components via additionalconnection pads. For example, as shown in FIG. 4A, the chip 410 can beconnected to an antenna lead, which can be formed of a patternedconductive material, such as electroplated gold, for example, thatsubstantially circles the substrate 405 to create a loop antenna.

FIG. 4B illustrates the arrangement in FIG. 4A when embedded in apolymeric material with a channel 450 positioned to expose theelectrochemical sensor electrodes 420, 430. In FIG. 4B, the polymericmaterial is illustrated by the hash pattern that is superimposed overthe portion of the substrate 405 shown in FIG. 4A. The channel 450 maybe formed by removing a portion of the encapsulating polymeric material(e.g., by etching, by removing a layer defined by a photoresist, etc.).The channel 450 exposes a region including the sensor electrodes 420,430, such that tear film coating the polymeric material is able tocontact the sensor electrodes 420, 430, and an analyte therein is ableto electrochemically react at the electrodes.

While not specifically illustrated in FIG. 4A-4B, the electrochemicalsensor may also include a reagent layer that immobilizes a suitablereagent near the working electrode 420 so as to sensitize theelectrochemical sensor to urea. In some examples, this reagent layertakes the form of a nano-powder of a pH-sensitive material disposed onthe working electrode 420 in the channel 450 positioned to expose theelectrochemical sensor electrodes 420, 430 to a tear film. Thenano-powder can be composed of zinc oxide, iridium oxide, or anotherpH-sensitive material. The reagent localized within the reagent layercan be comprised of urease. The urease can react with urea in the tearfilm to which the sensor electrodes 420, 430 are exposed, creating atleast ammonia. The reagent can be localized within the reagent layer bybeing adsorbed or otherwise bonded to the surface of the particles ofthe nano-powder disposed on the working electrode 420. In some examples,the working electrode 420 comprises platinum and the reference electrode430 comprises silver/silver chloride. The embodiments above are meantonly as illustrative examples; other reagent layer compositions,urease-selective reagents, electrode materials, and nano-powdercompositions are anticipated.

Moreover, it is particularly noted that while the electrochemical ureasensor platform is described herein by way of example as aneye-mountable device or an ophthalmic device, it is noted that thedisclosed electrochemical urea sensor and electrode arrangementstherefore can be applied in other contexts as well. For example,electrochemical urea sensors disclosed herein may be included inwearable (e.g., body-mountable) and/or implantable potentiometric ureasensors. In some contexts, an electrochemical urea sensor is situated tobe substantially encapsulated by bio-compatible polymeric materialsuitable for being in contact with bodily fluids and/or for beingimplanted. In one example, a mouth-mountable device includes anelectrochemical urea sensor and is configured to be mounted within anoral environment, such as adjacent a tooth or adhered to an inner mouthsurface. In another example, an implantable medical device that includesan electrochemical urea sensor may be encapsulated in biocompatiblematerial and implanted within a host organism. Such body-mounted and/orimplanted electrochemical urea sensors can include circuitry configuredto operate a potentiometric sensor by measuring a voltage across sensorelectrodes. The electrochemical urea sensor can also include an energyharvesting system and a communication system for wirelessly indicatingthe sensor results (i.e., measured voltage). In other examples,electrochemical urea sensors disclosed herein may be included inwireless potentiometric urea sensors which are not used to measure aurea concentration in or on a human body. For example, electrochemicalurea sensors disclosed herein may be included in body-mountable and/orimplantable potentiometric urea sensors used to measure a ureaconcentration in a fluid of an animal. In another example,electrochemical urea sensors disclosed herein may be included in devicesto measure a urea concentration in an environmental fluid, such as afluid in a river, lake, marsh, reservoir, water supply, sanitary sewersystem, or storm sewer system. In another example, electrochemical ureasensors disclosed herein may be included in devices to measure a ureaconcentration in a fluid which is part of a process, such as a wastetreatment process, pharmaceutical synthesis process, food preparationprocess, fermentation process, or medical treatment process

V. Example Processes for Measuring Urea Concentration in a Fluid

FIG. 5 is a flowchart of a process 500 for operating a potentiometricelectrochemical urea sensor in a body-mountable device to measure a ureaconcentration in a fluid of a body. The body-mountable device is mountedon the body such that a working electrode and a reference electrode ofthe device are exposed to a fluid of the body (502). For example, thebody-mountable device could be formed to substantially conform to acornea of an eye of the body, and the device could be mounted on thecornea such that the working electrode and reference electrode of thedevice are exposed to a tear film of the eye. A potentiometric voltageis measured between the working electrode and the reference electrode onthe electrochemical sensor (504). For example, a high-impedancevoltmeter can measure a voltage between the working and referenceelectrodes while substantially preventing the flow of current throughthe working and reference electrodes. In an example embodiment, theworking electrode can be a platinum electrode and the referenceelectrode can be a silver/silver chloride electrode, and a reagent thatselectively reacts with urea to create at least ammonium hydroxide canbe localized proximate to the working electrode. The measuredpotentiometric voltage is wirelessly indicated (506). For example,backscatter radiation can be manipulated to indicate the sensor resultby modulating an impedance of an antenna.

FIG. 6 is a flowchart of a process 600 for operating an external readerto interrogate a ptentiometric electrochemical urea sensor in abody-mountable device to measure a urea concentration of a fluid thatthe device is exposed to. Radio frequency radiation is transmitted to abody-mountable device from the external reader (602). The transmittedradiation is sufficient to power the electrochemical urea sensor withenergy from the radiation for long enough to perform a measurement ofurea concentration and communicate the results (602). For example, theradio frequency radiation used to power the electrochemical urea sensorcan be similar to the radiation 341 transmitted from the external reader340 to the body-mountable device 310 described in connection with FIG. 3above. The external reader then receives a radio frequency signal fromthe body-mountable device indicating the measurement by theelectrochemical urea sensor (604). For example, the radio frequencysignal could be backscatter radiation similar to the backscatter signals343 sent from the body-mountable device 310 to the external reader 340described in connection with FIG. 3 above. The backscatter radiationreceived at the external reader is then associated with a fluid ureaconcentration (606). In some cases, the urea concentration values can bestored in the external reader memory (e.g., in the processing system346) and/or a network-connected data storage. In some cases, the ureaconcentration value can be indicated on a display of the reader device.In some cases, the urea concentration may be measured at a plurality ofpoints in time.

For example, the sensor result (e.g., the measured potentiometricvoltage) can be encoded in the backscatter radiation by modulating theimpedance of the backscattering antenna. The external reader can detectthe antenna impedance and/or change in antenna impedance based on afrequency, amplitude, and/or phase shift in the backscatter radiation.The sensor result can then be extracted by associating the impedancevalue with the sensor result by reversing the encoding routine employedwithin the body-mountable device. Thus, the reader can map a detectedantenna impedance value to a potentiometric voltage value. Thepotentiometric voltage value is approximately proportionate to fluidurea concentration with a sensitivity (e.g., scaling factor) relatingthe potentiometric voltage and the associated fluid urea concentration.This urea concentration could then be indicated to a user of the readerby displaying the measured urea concentration on a display disposed onthe reader. The sensitivity value can be determined in part according toempirically derived calibration factors, for example.

VI. Example Method for Fabricating a Body-Mountable Urea Sensor

FIG. 7 is a flowchart of an example process 700 for fabricating abody-mountable device capable of potentiometrically measuring a ureaconcentration in a fluid. A substrate is formed (702) to provide a basestructure for the fabrication of the device. The substrate can be arelatively rigid material, such as polyethylene terephthalate (“PET”),parylene, or another material configured to structurally supportelectrical components of an electrochemical urea sensor within a shapedpolymeric material. In examples where the body-mountable device ismounted to a cornea of an eye, the substrate may be shaped as aflattened ring with a radial width dimension sufficient to provide amounting platform for embedded electronics components. The substrate canoptionally be aligned with a curvature of the cornea of the eye (e.g.,convex surface). For example, the substrate can be shaped along thesurface of an imaginary cone between two circular segments that definean inner radius and an outer radius. In such an example, the surface ofthe substrate along the surface of the imaginary cone defines aninclined surface that is approximately aligned with the curvature of theeye mounting surface at that radius. When the device is mounted to theeye, this example substrate does not interfere with vision because it istoo close to the eye to be in focus and is positioned away from thecentral region where incident light is transmitted to the eye-sensingportions of the eye. Other materials and shapes of the substrate areanticipated according to applications of a body-mountable ures sensingdevice. The substrate may be formed into a single piece or multiplepieces later embedded in a single shaped polymeric material to form thebody-mountable device.

Components are disposed on the substrate (704). Components may includeloop antennas, electronic components, interconnects, and electrodes. Theinterconnects, loop antennas, and electrodes can be formed fromconductive materials patterned on the substrate by a process forprecisely patterning such materials, such as deposition,photolithography, etc. The conductive materials patterned on thesubstrate can be, for example, gold, platinum, palladium, titanium,carbon, aluminum, copper, silver, silver-chloride, conductors formedfrom noble materials, metals, combinations of these, etc. In someembodiments, some electronic components can be mounted on one side ofthe substrate, while other electronic components are mounted to theopposing side, and connections between the two can be made throughconductive materials passing through the substrate. Components such aselectronic chips may be disposed on the substrate and connected to theother components by methods familiar to one skilled in the art (e.g.,pick-and-place machines, flip-chip mounting). The components include atleast a working electrode and a reference electrode which can beconfigured to sense the concentration of urea in a fluid to which thebody-mountable device is exposed. The electrodes can be disposed on thesubstrate as described above.

The substrate and components disposed thereon are at least partiallyembedded in a shaped polymeric material (706). In examples where thebody-mountable device is mounted to a cornea of an eye, the shapedpolymeric material can be shaped as a curved disk. The polymericmaterial can be a substantially transparent material to allow incidentlight to be transmitted to the eye while the body-mountable device ismounted to the eye. The polymeric material can be a biocompatiblematerial similar to those employed to form vision correction and/orcosmetic contact lenses in optometry, such as polyethylene terephthalate(“PET”), polymethyl methacrylate (“PMMA”), polyhydroxyethylmethacrylate(“polyHEMA”), silicone hydrogels, combinations of these, etc. Thepolymeric material can be formed with one side having a concave surfacesuitable to fit over a corneal surface of an eye. The opposite side ofthe disk can have a convex surface that does not interfere with eyelidmotion while the body-mountable device is mounted to the eye. In someembodiments, the dimensions of the shaped polymeric material of thebody-mountable device can be selected according to the size and/or shapeof the corneal surface of a wearer's eye.

The polymeric material can be formed in a variety of ways. For example,techniques similar to those employed to form vision-correction contactlenses, such as heat molding, injection molding, spin casting, etc. canbe employed to form the shaped polymeric material. In examples where theshaped polymeric material is shaped to be mounted to a cornea of an eyethe substrate and components disposed thereon can be embedded to besituated along the outer periphery of the curved disk shape of thepolymeric material, away from a central region. The substrate andcomponents disposed thereon do not interfere with vision because theyare too close to the eye to be in focus and are positioned away from thecentral region where incident light is transmitted to the eye-sensingportions of the eye. Moreover, the substrate can be formed of atransparent material to further mitigate effects on visual perception.Partially embedding the substrate and components disposed thereon canmean covering the substrate and components thereon except for a workingelectrode and reference electrode of an electrochemical urea sensor, sothat only the working electrode and reference electrode of the ureasensor are in direct contact with the fluid to which the body-mountabledevice is exposed. In some embodiments, other components or parts of thesubstrate are not covered by the shaped polymeric material. For example,more than one electrochemical sensor may be disposed on the substrate,and the electrodes associated with the more than one sensor may not becovered by the shaped polymeric material.

A reagent that selectively reacts with urea is localized proximate to aworking electrode disposed on the substrate (708). In some examples, asolution including urea-selective reagents, a pH-sensitive metal oxidenano-powder, water, and alcohol is synthesized, applied to the workingelectrode, and the water and alcohol are evaporated leaving theparticles of the nano-powder disposed on the working electrode and theurea-selective reagent adsorbed on the particles of the nano-powder. Theurea-selective reagent can include urease. The pH-sensitive metal oxidecan include zinc oxide, iridium oxide, tin oxide, cerium oxide, or othermaterials or combinations of materials. Other solutions are anticipated,wherein different pH-sensitive materials, aqueous or non-aqueoussolvents, or urea-selective reagents are used according to theapplication of fabricating a body-mountable device to detect ureaconcentration in a fluid. For example, the pH-sensitive metal oxide maytake the form of nanowires or may be coated on the surface of theworking electrode by plating, deposition, or some other method. Aprotective layer can be formed over the urea-selective reagent layer.This layer can be composed of a urea-permeable polymer or some othermaterial which is permeable to urea and which can be deposited on thereagent layer while leaving the ability of the reagent layer to detecturea substantially intact.

CONCLUSION

While various aspects and embodiments have been disclosed herein, otheraspects and embodiments will be apparent to those skilled in the art.The various aspects and embodiments disclosed herein are for purposes ofillustration and are not intended to be limiting, with the true scopebeing indicated by the following claims.

Further, where example embodiments involve information related to aperson or a device of a person, some embodiments may include privacycontrols. Such privacy controls may include, at least, anonymization ofdevice identifiers, transparency and user controls, includingfunctionality that would enable users to modify or delete informationrelating to the user's use of a product.

In situations in where embodiments discussed herein collect personalinformation about users, or may make use of personal information, theusers may be provided with an opportunity to control whether programs orfeatures collect user information (e.g., information about a user'smedical history, social network, social actions or activities,profession, a user's preferences, or a user's current location), or tocontrol whether and/or how to receive content from a content server thatmay be more relevant to the user. In addition, certain data may betreated in one or more ways before it is stored or used, so thatpersonally identifiable information is removed. For example, a user'sidentity may be treated so that no personally identifiable informationcan be determined for the user. Thus, the user may have control over howinformation is collected about the user and used by a content server.

What is claimed is:
 1. A body-mountable device comprising: a shapedpolymeric material; a substrate at least partially embedded within theshaped polymeric material; an antenna disposed on the substrate; anelectrochemical sensor disposed on the substrate and comprising: aworking electrode; a reagent that selectively reacts with urea, whereinthe reagent is localized proximate to the working electrode; and areference electrode; and a controller electrically connected to theelectrochemical sensor and the antenna, wherein the controller isconfigured to: (i) measure a potentiometric voltage between the workingelectrode and the reference electrode related to the concentration ofurea in a fluid to which the body-mountable device is exposed; and (iii)use the antenna to indicate the measured potentiometric voltage.
 2. Thebody-mountable device according to claim 1, wherein the fluid is a tearfluid of an eye, wherein the shaped polymeric material has a concavesurface and a convex surface, wherein the concave surface is configuredto be removably mounted over a corneal surface and the convex surface isconfigured to be compatible with eyelid motion when the concave surfaceis so mounted.
 3. The body-mountable device according to claim 1,further comprising a pH-responsive oxide localized proximate to theworking electrode.
 4. The body-mountable device according to claim 3,wherein the pH-responsive oxide is in the form of a nano-powder, whereinthe reagent that selectively reacts with urea is disposed on theparticles of the nano-powder.
 5. The body-mountable device according toclaim 3, wherein the pH-responsive oxide includes zinc oxide or iridiumoxide.
 6. The body-mountable device according to claim 1, wherein thereagent comprises urease.
 7. The body-mountable device according toclaim 1, wherein the working electrode comprises platinum and thereference electrode comprises silver/silver-chloride.
 8. Thebody-mountable device according to claim 1, wherein the antenna isconfigured to receive radio frequency energy to power the body-mountabledevice.
 9. The body-mountable device according to claim 1, wherein usingthe antenna to indicate the measured potentiometric voltage comprisessending a radio frequency signal.
 10. The body-mountable deviceaccording to claim 1, wherein using the antenna to indicate the measuredpotentiometric voltage comprises reflecting a radio frequency signal.11. A method comprising: exposing a working electrode and a referenceelectrode to a fluid, wherein the working electrode and referenceelectrode are disposed in a body-mountable device, wherein the workingelectrode is selectively sensitive to urea, wherein the body-mountabledevice additionally includes an antenna and measurement electronics, andwherein the working electrode, reference electrode, antenna, andmeasurement electronics are disposed on a substrate that is at leastpartially embedded in a shaped polymeric material; measuring apotentiometric voltage between the working electrode and the referenceelectrode related to the concentration of urea in a fluid to which thebody-mountable device is exposed; and wirelessly indicating the measuredvoltage using the antenna.
 12. The method of claim 11, wherein the fluidis a tear fluid of an eye, and wherein the shaped polymeric material hasa concave surface and a convex surface, wherein the concave surface isconfigured to be removably mounted over a corneal surface of the eye andthe convex surface is configured to be compatible with eyelid motionwhen the concave surface is so mounted.
 13. The method of claim 11,wherein measuring the potentiometric voltage and wirelessly indicatingthe measured voltage using the antenna are performed in response to aninterrogating radio frequency signal received by the antenna.
 14. Themethod of claim 13, where the interrogating radio frequency signal isused to power the body-mountable device.
 15. The method of claim 13,wherein wirelessly indicating the measured voltage comprises reflectinga version of the interrogating radio frequency signal.
 16. A systemcomprising: an antenna configured to wirelessly communicate with abody-mountable device, wherein the body-mountable device is configuredto measure a voltage related to the concentration of urea in a fluid towhich the body-mountable device is exposed; a processor; and anon-transitory computer readable medium containing instructions that,when executed by the processor, cause the system perform functionscomprising: (i) using the radio frequency antenna to interrogate thebody-mountable device by transmitting a radio frequency signal, (ii)receiving from the body-mountable device a radio-frequency signalindicating a measured voltage, (iii) determining a urea concentration inthe fluid based on the indicated measured voltage.
 17. The system ofclaim 16, wherein the transmitted radio frequency signal is sufficientto power the body-mountable device.
 18. The system of claim 16, furthercomprising: a display; and wherein the functions further comprise (iv)indicating the determined urea concentration on the display.
 19. Thesystem of claim 16, further comprising a communication interface,wherein the communication interface is configured to transmit theindicated measured voltage and/or determined urea concentration toanother device.
 20. A method comprising: interrogating a body-mountabledevice, the body-mountable device including an antenna, measurementelectronics, and an electrochemical sensor with a working electrode anda reference electrode, wherein a reagent that selectively reacts withurea is localized proximate to the working electrode, wherein theantenna, measurement electronics, and the electrochemical sensor aredisposed on a substrate that is at least partially embedded in a shapedpolymeric material, by transmitting radio frequency radiation sufficientto power the electrochemical sensor and measurement electronics tomeasure a voltage difference between the working electrode and thereference electrode related to urea; receiving, from the body-mountabledevice, a radio frequency signal indicating the measured voltage; anddetermining a concentration of urea based on the measured voltageindicated by the radio frequency signal.
 21. The method of claim 20,wherein receiving a radio frequency signal comprises receiving areflected version of the transmitted radio frequency radiation.
 22. Themethod of claim 20, further comprising: displaying an indication of thedetermined concentration of urea.
 23. The method of claim 20, whereinthe concentration of urea near the working electrode is determined atmultiple points in time.
 24. The method of claim 23, further comprising:determining the concentration of urea at multiple points in time.
 25. Amethod comprising: forming a substrate; disposing components on thesubstrate, wherein the components include an electrochemical sensorhaving at least a working electrode and a reference electrode,measurement electronics, and a radio frequency antenna; at leastpartially embedding the substrate and components disposed thereon in ashaped polymeric material; and localizing a reagent that reactsselectively with urea proximate to the working electrode.
 26. The methodof claim 25, wherein the shaped polymeric material has a concave surfaceand a convex surface, wherein the concave surface is configured to beremovably mounted over a corneal surface of the eye and the convexsurface is configured to be compatible with eyelid motion when theconcave surface is so mounted.
 27. The method of claim 25, wherein atleast partially embedding the substrate and components disposed thereonin a shaped polymeric material comprises covering the substrate andcomponents disposed thereon with the polymeric material except for theworking electrode and reference electrode of the electrochemical sensor.28. The method of claim 25, wherein the reagent comprises urease. 29.The method of claim 25, further comprising: localizing a nano-powdercomprising a pH-sensitive oxide proximate to the working electrode. 30.The method of claim 29, wherein localizing a reagent that reactsselectively with urea proximate to the working electrode and localizinga nano-powder comprising a pH-sensitive oxide proximate to the workingelectrode comprise: creating a mixture comprising a nano-powder of thepH-sensitive oxide, the reagent that reacts selectively with urea,water, and alcohol; depositing the mixture on the surface of the workingelectrode; and evaporating the water and alcohol.